Process for the preparation of 3-aryl-2-imino-3-indolinols and related compounds

ABSTRACT

A NEW PROCESS IS DISCLOSED REACTING A 2-BENZOYL ACYLANILIDE WITH IONIC CYANIDES TO FORM NEW 3-ARYL-2-IMINO-3INDOLINOLS AND 2-AMINO-3-ARYL-3H-INDOL-3-OLS. THESE PRODUCTS MAY BE FURTHER REACTED TO FORM A NUMBER OF NEW DERIVATIVES WHICH HAVE PHARMACOLOGICAL ACITIVITY AS CENTRAL NERVOUS SYSTEM DEPRESSANTS.

United States Patent PROCESS FOR THE PREPARATION OF 3-ARYL-2-IMINO-S-INDOLINOLS AND RELATED COM- POUNDS Stanley C. Bell, Nat-berth,and Carl Gochman, Philadelphia, Pa., assignors to American Home ProductsCorporation, New York, N.Y.

No Drawing. Continuation-impart of application Ser. No. 694,066, Dec.28, 1967. This application Aug. 14, 1968, Ser. No. 752,488

Int. Cl. C07d 27/38 U.S. Cl. 260-32611 9 Claims ABSTRACT OF THEDISCLOSURE A new process is disclosed reacting a 2-benz0yl acylanilidewith ionic cyanides to form new 3-aryl-2-imino-3- indolinols and2-amino-3-aryl-3H-indol-3-ols. These products may be further reacted toform a number of new derivatives which have pharmacological activity ascentral nervous system depressants.

This application is a continuation-in-part of application Ser. No.694,066, filed Dec. 28, 1967 and entitled A Process for the Preparationof 3-Aryl-2-Imino-3-Indolinols and 2-Amino-3-Aryl-3H-Indol-3-Ols.

This invention relates to new 3-aryl-2-imino-3-indolinols andZ-amino-3-aryl-3H-indol-3-ols and their derivatives, and to a newprocess for their preparation by reacting a 2-benzoyl acylanilide withan ionic cyanide.

The new and novel compounds within the purview of the present inventionare exemplified by those having the following formula:

and R and R are the same or different members selected from the groupconsisting of hydrogen, halogen, lower alkyl and lower alkoxy;

R and R are the same or dilferent members selected from the groupconsisting of hydrogen and sulfamoyl;

R is selected from the group consisting of hydrogen, lower alkyl, loweralkylamino(lower)alkyl; di(lower)- alkylamino (lower) alkyl;

R is selected from the group consisting of hydrogen and lower alkyl,with the proviso that R is hydrogen when W is structure (C);

R is selected from the group consisting of hydrogen, lower alkyl, loweralkanoyl, halo (lower) alkanoyl and dihalo (lower) alkanoyl;

With the proviso that when R is other than hydrogen and lower alkyl, Rand R are hydrogen;

With the proviso that when R R and R are lower alkyl, they are the same;and

With the further proviso that R and R' are hydrogen when R is eitherloweralkylamino (lower) alkyl, or di- (lower) alkylamino (lower) alkyl.

As used herein the terms lower alkyl, lower alkoxy, and the likedescribe groups containing from one to about eight carbon atoms.

Typical examples of the compounds of this invention which are depictedby structural Formula IB are:

S-chloro-1-(2,2-dichloroacetyl) 2 imino-3-(m-sulfamoylphenyl)-3-indolinol;

5-chloro-3-(2-chloro 5 sulfamoylphenyl)-1-(2,2-dichloroacetyl-2-imino-3-indolinol.

Alternatively, the compounds of this invention which are represented bystructural Formula IA are typified by:

2-amino-5-chloro-3-phenyl-3H-indol-3-ol; and 2-amino-5-chloro-3-(m-sulfamoylphenyl) -3H-indol-3-ol.

Still further typical examples of the compounds of this inventionillustrated by structural Formula IC are:

4-chloro-3- 5-chloro-2-hydrazino-3 -hydroxy-3H-indol- 3-yl)-benzenesulfonamide;

3-(2-hydrazino-3-hydroxy-3H-indol-3-yl) -benzenesulfonamide;

3-(4-chlorophenyl)-2hydrazine-5-methoxy-3H-indol-3-ol;

and

2-hydrazino-6-methyl-3-(4-tolyl)-3H-indol-3-ol.

The compounds of this invention designated by structural Formulas LA andIB are tautomers Where R and R are hydrogen.

The compounds of this invention designated by structural Formula IA arecalled 2-alkylaminoalkylamino-3- aryl-3H-indol-3-ols when R is hydrogenand R is lower alkylamino(lower)alkyl or di(lower)alkylamino(lower)alkyl, for example,5-chloro-2-[2-(dimethylamino)ethylamino]-3-phenyl-3H-indol-3-ol. Thecompounds of this invention designated by structural Formula IA arecalled 3-alkoxy-2-alkylamino-3-arylindoles where R and R are loweralkyl, for example, S-chloro-3-methoxy-2-methylamino-3-phenylindole. Thecompounds of this invention designated by structural Formula IA arecalled 2-alkylamino-3-arylindol-3-ols, when R is lower alkyl and R ishydrogen, for example 5-chloro-2-methylamino-3- phenyl-3-indol-3-ol.

The compounds of this invention designated by structural Formula IB arecalled 2-alkylaminoalkylimino-3- arylindolinols where R is loweralkylamino(lower)alky1 or di(lower) alkylamino(lower)alkyl and R and Rare hydrogen, for example 5-chloro-2-[Z-(dimethylamino)ethylimino]-3-phenyl-3H-indolinol. The compounds of this inventiondesignated by structural Formula B are called2-alkylamino-3-arylindolinols where R is lower alkyl and R and R arehydrogen, for example, S-chloro- 2-methylimino-3-phenyl-3-indolinol. Thecompounds of this invention designated by structural Formula T8 arecalled 3-alkoxy-2-alkylimino-3-arylindolines where R and R are loweralkyl and R is hydrogen, for example,5-chloro-3-methoxy-2-methylimino-3-phenylindoline. The compounds of thisinvention designated by structural Formula -IB are called 3-alloxy-1-alky1-2-alkylimino-3 arylindolines, where R R and R are loweralkyl, for example S-chloro 3 methoxy-l-methyl-Z-methylimino-3-phenylindoline.

The compounds of this invention designated by structural Formula 10 arecalled 3-aryl-2-hydrazino-3H-indol- 3-ols, for example,Z-hydrazinofi-methyl-S-(4-tolyl)-3H- indol-3-ol.

C OR

a N NHCOR NHOOR NH R E i CN R R2 l R2 o== H OH NE NH I KCN I cychzatlonI 2 2 R 33 R R3 R 4 R R (VII) Where R R' are defined as above;

R is selected from the group consisting of lower alkyl, halo (loweralkyl, and dihalo (lower) alkyl;

R is selected from the group consisting of hydrogen and lower alkyl;

R is lower alkyl; and

R is selected from the group consisting of lower alkylamino (lower)alkyl, and di (lower) alkylamino (lower) alkyl.

The 2-benzoylacylanilides which are used as starting materials toprepare the compounds of the present invention may be prepared asdescribed in United States patent application Ser. No. 704,585 filedFeb. 12, 1968 by Stanley C. Bell and titled5,5'-Disulfamoylbenzophenones and now allowed, as US. Pat No. 3,526,646.

In preparing the compounds of the present invention a 2-benzoylacylanilide (II) is mixed with an ionic cyanide in the presence of aproton donor, such as water. The mechanism of the process is believed toinclude the formation of an intermediate (III) which is not separated orrecovered. After a predetermined period as hereinafter set forth thereaction mixture is concentrated to dryness, and the residue dissolvedin water. The solution is acidified, for example, with acetic acid, anda solid containing a mixture of compounds (IV) and (V) precipitates. Themixture is suspended in an acid, such as dilute hydrochloric acid, andfiltered. The collected solid is an appropriate3-aryl-2-imino-3-indolinol (IV). The filtrate is then neutralized with abase, for instance with sodium carbonate, and the resulting precipitateis a 2-amino-3- aryl-3H-ind0l-3-ol (V) which may be further purified byrecrystallization from an alcohol-water solvent.

The ionic cyanide employed as a reactant in the above reaction may besodium cyanide, lithium cyanide, calcium cyanide, cuprous cyanide or,preferably, potassium cyanide. The reaction is preferably carried out inan organic solvent that is miscible with the proton donor and does notreact with the ionic cyanide. Such solvents include alkanols, dioxane,dimethoxyethane and the like, ethanol being preferred. The reaction iscarried out at a temperature between about 0 to 50 C. for betweenonequarter of an hour and seventy-two hours. When the reaction isconducted at relatively lower temperatures and shorter time periods, theresulting mixture of products contains a preponderance of a3-aryl-2-imino-3-indolinol (IV). Alternatively, when the reaction isconducted at relatively higher temperatures and longer time periods, theresulting mixture of the products contains a preponderance of a2-amino-3-aryl-3H-indol3-ols (V). The latter reaction and the method ofseparating the 2-amino-3- aryl-3H-indol-3-ols is exemplified in Example1.

hydrolysis NN 1 R2 l alkylatlon alkylation (V) VIII) The3-ary1-2-imino-3H-indol-3-ols (IV) which are separated from the abovereaction may be hydrolyzed by conventional procedures to form thecorresponding Z-amino- 3-aryl-3H-indol-3-ols (V), for instance by mixingwith an ionic cyanide, or a strong base, such as sodium hydroxide, forabout 15 minutes to about 10 hours at about room temperature to about 50C.

The 2-amino-3-aryl-3H-indol-3-ols (V) are useful as intermediates in thepreparation of compounds of United States patent application Ser. No.694,089 filed Dec. 28, 1967 by Stanley C. Bell et al. and entitled2-Acylamido- 3-Aryl-3H-Indol-Ol Esters and Related Compounds, which wasabandoned and refiled as application Ser. No. 7,304 on Jan. 13, 1970.The latter compounds have central nervous system activity asdepressants. That is, they produce a calming elfect in the host.

To prepare a 2 alkylaminoalkylamino-3-aryl-3H-indol- 3-01 (VIII) a2-amino-3-aryl-3H-indol-3-ol (V) is heated at a temperature range ofabout C. to about reflux temperatures for a period of about one-half toabout six hours, with a di(lower)alkylamino(lower)alkyl halide or alower alkylamino (lower)alkylhalide, such as dialkylaminoalkylchloride,for instance, dime'thylaminoethylchloride, and a non-reactive base suchas tri-substituted amines, particularly a trialkylamine, for instancetriethylamine. In this reaction an appropriate hydrohalide may besubstituted for the di(lower)alkylamino(lower)alkylhalide or loweralkylamino(lower)alkylhalide. When the reaction is complete, thereaction mixture is diluted with a large volume of water. Thereafter,the supernatant liquid is removed by decantation and the insoluble2-alkylaminoalkylamino- 3-aryl-3I-I-indole-3-ol (VIII) is recovered bywell-known techniques. For instance, the insoluble product may besuspended in an acidic medium such as dilute acetic acid and thenfiltered. Thereafter, the filtrate may be neutralized, for instance,with sodium carbonate or potassium carbonate and then recrystallizedfrom a lower alcohol such as ethanol. If desired, the free base,2-alkylaminoalkylamino-3-aryl-3H-indol-3-ol (VIII), may be converted toits corresponding mineral acid salt e.g., the hydrochloride salt bycontact with an appropriate mineral acid in ether and thenrecrystallized from ethanol.

The products of this invention having structural Formula VI where R", Ror R are alkyl may be prepared by the following procedure. A2-amino-3-aryl-3H-indol 3-01 (V) is suspended in a protionic solvent,such as an alkanol, preferably ethanol. To the suspension is added apredetermined amount of a basic catalyst, such as potassium hydroxide,sodium hydroxide, sodium bicarbonate, potassium carbonate and the like.Then an alkylating agent, such as sulfate esters, for instancedimethylsulfate and diethylsulfate, arylsulfonate esters, for instance,methyl-p-toluenesulfonate, alkyl halides, for instance, methyl bromide,etc, is added until the reaction mixture is no longer basic. Thereaction mixture is then made basic, for instance with sodium hydroxide,and diluted with water to yield the product. The product may berecovered by well known procedures. For instance, the product may befiltered and recrystallized, for instance from an ethanolwater mixture,to obtain the pure product.

The relative amounts of basic catalyst, alkylating agent, and3-aryl-3H-indol-3-ol *(V) determine whether the product will have one,two or three alkyl substituents. The preponderance of the productcontains 3-alkyl groups when three equivalents of basic catalyst andalkylating agent are used with relation to the 2-amino3-aryl-3H-indol-3-ol, the product being a3-alkoxy-1-alkyl-2-alkylimino-3-arylindoline.

When about 1.5 equivalents of basic catalyst and alkylating agent, basedon the 2-amino-3-aryl-3H-indol-3- 01 (V) are used, the product consistspredominantly of a mixture of monoalkyl and dialkyl substitutedproducts. The monoalkyl and dialkyl substituted products may beseparated from each other by well known means, For instance, the productmay be suspended in an organic medium such as acetonitrile.Recrystallization from the organic medium affords the monoalkylsubstituted product a 2-alkylimino-3-arylindolinol.

The solution from which the latter product is obtained may beconcentrated to dryness to afford the crude dialkyl-substituted product,a 3-alkoxy-2-alkylimino-3-arylindoline. Recrystallization from analcohol-water mixture and then from hexane affords the purified dialkylsubstituted product.

The 3-aryl-2-hydrazino 3H indol-3-ol compounds, (VII) of this inventionare prepared by contacting an appropriate 3-aryl-2-imino-3-indolinol(IV), or 3-aryl- 3H-indol-3-ol (V) with hydrazine in a reaction-inertsolvent at a temperautre range from about 60 C. to about 100 C. for aperiod of 30 minutes to four hours using a 3-aryl-2-imino-3-indolinol(IV) or for a period of about fifteen minutes to about sixty minutesusing a 3H-indol- 3-01 (V). Preferably this reaction is conducted usinga 2-amino-3-aryl-3H-indol-3-ol in water at about steam bath temperaturesfor a period of about one-half hour.

When the reaction is complete, the resulting 3-aryl-2-hydrazino-3H-indol-3-ol (VII) is separated by standard recoveryprocedures. For example, the reaction mixture is cooled, diluted,acidified with an organic acid, e.g. acetic acid, filtered and thecollected solid is recrystallized from a suitable solvent, e.g., analkanol-water mixture.

By a reaction-inert solvent as employed herein is meant a liquid whichwill dissolve the reactants and not interfere with their interaction.Many such solvents will readily suggest themselves to one skilled in theart of chemistry, e.g. Waters and alkanols.

The 2-alkylaminoalkylamino-3-aryl-3H-indol-3-ols and2-alkylaminoalkylimino-3-arylindolinols of this invention have utilityas central nervous system depressants. That is, they produce a calmingeffect in the host.

In the pharmacological evaluation of the biological activity of thecompounds of this invention, the in vivo effects are tested as follows.The compound is administered orally or intraperitoneally to three mice(14 to 24 grams) at each of the following doses: 400, 127, 40 and 12.7mg./kg. of mouse body weight (MPK). The animals are watched for aminimum of two hours durin which time signs of general stimulation(i.e., increased spontaneous motor activity, hyperactivity on tactilestimulaiton, twitching), general depression (i.e., decreased spontaneousmotor activity, decreased respiration) and autonomic activity (i.e.,miosis, mydriasis, diarrhea) are noted, The compounds of Formulas VI,VII and VIII of this invention are depressants in the dose range from127 MPK administered orally to 400 MPK administered intraperitioneally.The compounds of Formula IV and V are intermediates in the preparationof compounds that have such activity. Some of the compounds of Formula Valso have depressant activity.

When the compounds of this invention are employed as described above,they may be administered alone or in combination with pharmacologicallyacceptable carriers, the proportion of which is determined by thesolubility and chemical nature of the compound, chosen route ofadministration and standard pharmocological practice. For example, theymay be administered orally in the form of tablets or capsules containingsuch excipients as starch, milk, sugar, certain types of clay and soforth. They may be administered suhlingually in the form of troches orlozenges in which the active ingredient is mixed with sugar and cornsyrups, and then dehydrated sutficiently to make it suitable forpressing into a solid form. They may be administered orally in the formof solutions which may contain coloring and flavoring agents or they maybe injected parenterally, that is intra-muscularly, intravenously orsubcutaneously. For parenteral administration they may be used in theform of a sterile solution containing other solutes, for example, enoughsaline or glucose to make the solution isotonic.

The dosage of the present therapeutic agents will vary with the form ofadministration and the particular compound chosen. Furthermore, it willvary with the particular subject under treatment. Generally, treatmentis initiated with small dosages substantially less than the optimum doseof the compound. Thereafter, the dosage is increased by small incrementsuntil the optimum effect under the circumstances is reached. It willgenerally be found that when the composition is administered orally,larger quantities of the active agent will be required to produce thesame effect as a smaller quantity given parenterally. In general, thecompounds of this invention are most desirably administered at aconcentration level that will generally afford effective results withoutcausing any harmful or deleterious side effects.

In order more clearly to disclose the nature of the pres ent invention,specific examples of the practice of the invention are hereinaftergiven. It should be understood, however, that this is done solely by wayof example and is intended neither to delineate the scope of theinvention nor limit the ambit of the appended claims.

EXAMPLE 1 This example illustrates the preparation of 2-amino-5-chloro-3-phenyl-3H-indol-3-ol, a compound of Formula V, from a compoundof Formula II.

To a suspension of 10.0 grams (g.) of 2'-benzoyl-2,2,4'-trichloroacetanilide in 150 milliliters (ml.) of ethanol is added asolution of 6.0 g. of potassium cyanide in 50 ml. of water. Afterstirring about 16 hours the reaction mixture is filtered from insolublematerial and diluted with water to precipitate 7.0 g. of product.Recrystallization from acetonitrile gives the pure compound, Z-amino-S-chloro-3-phenyl-3H-indol-3-ol, having a melting point (M.P.) of 2l5217C.

Based on the formula C H CIN O it was calculated that the elementalanalysis by weight would be 64.99 percent carbon, 4.29 percent hydrogen,10.83 percent nitrogen, and 13.20 percent chlorine. The product wasanalysed and the content was found to be 65.02 percent carbon, 3.98percent hydrogen, 10.70 percent nitrogen and 13.70 percent chlorine. Theforegoing may be expressed:

Analysis. Calcd. for C H CIN O (percent): C, 64.99; H, 4.29; N, 10.83;Cl, 13.20. Found (percent): C, 65.02; H, 3.98; N, 10.70; Cl, 13.70.

EXAMPLE 2 To a mixture of 13.6 g. of2-benzoyl-4,4'-dichlorobutyranilide, 1.0 g. of sodium iodide and ml. ofethanol is added 4.0 g. of potassium cyanide in 25 ml. of water, and thereaction mixture is stirred for 48 hours. Then 75 ml. of water are addedand the by-product removed by filtration. The lay-product is1-(2-benzoyl-4-chlorophenyl)- 2-pyrrolidinone. The filtrate is dilutedwith Water, and there is filtered off the same compound as prepared inExample 1: Z-amino-5-chloro-3-phenyl-3H-indol-3-ol.

EXAMPLE 3 To a mixture of 13.6 g. of 2'-benzoyl-4'-chlorohexanoylanilideand 125 ml. of dimethoxyethane is added a solution of 4.0 g. ofpotassium cyanide in 25 ml. of water. After stirring for 48 hours, thereaction mixture is diluted with 75 ml. of Water and filtered fromimpurities. The filtrate is diluted with a large volume of Water toprecipitate out the product which is the same as prepared by Example 1:Z-amino-5-chloro-3-phenyl-3H-indol-3-ol.

EXAMPLES 4-5 Proceeding as in Example 3, the following startingmaterials yield the following products:

Starting material Product Example:

5 2-(2-ethoxybenzoyl)-2, 2, 4- 2-amino-5-chloro-3 (2- triehloro-acetanilide. egthfxyphenyl) -3H-indo l- EXAMPLE 6 EXAMPLE 7 The followingexample illustrates the preparation, from a compound having Formula II,of compounds having Formulae IV and V, the latter being respectively,-chloro 1 (2,2 dichloroacetyl) 2 imino-3-(m-sulfamoylphenyl) 3 indolinoland 2-amino-5-chloro-3-(m-sulfamoylphenyl) -3H-indol-3-ol.

To a suspension of 34 g. of2,2,4'-trichloro-2'-(m-sulfamoylbenzoyl)acetanilide in 400 ml. ofethanol is added a solution of 20 g. of potassium cyanide in 100 ml. ofwater. After stirring at room temperature for 1% hours, the reactionmixture is concentrated to dryness and the residue dissolved in water.Acidification with acetic acid produces a solid which is suspended indilute hydrochloric acid and filtered from 15.4 g. of insolublematerial. Neutralization of the filtrate with sodium carbonate gives 5.7g. of product, 2-amino-5-chloro-3-(m-sulfamoylphenyl)-3H-indol-3-ol,which is recrystallized from an alcohol-water solution and has a meltingpoint of 216- 218 C. In infrared illumination the product has peaks at607 6.35,u, 7.72 1. and 8.57M.

Analysis.-Calcd. for C H ClN Cl S (percent): C, 49.78; H, 3.58; N,12.44; Cl, 10.49; S, 9.49. Found (percent): C, 49.81; H, 3.45; N,12.61;CI, 10.6; S, 9.6.

The 15.4 g. of above insoluble material is recrystallized from adi'methylformamide-Water solution, to yield S-chloro 1(2,2-dichloroacetyl)-2-imino-3-(m-sulfamoylphenyl)-3-indolinol, having amelting point of 269- 270 C. In infrared illumination, the product haspeaks at 5.84 6.14,.t, 6.26 1, 7.86;. and 8.80

Analysis.Calcd. for C H Cl N O S (percent): C, 42.82; H, 2.70; N, 9.36;Cl, 23.71; S, 7.15. Found (percent): C, 42.92; H, 2.58; N, 9.24; Cl,23.1; S, 7.1.

8 EXAMPLES 8-23 Following the above procedure of Example 7 andsubstituting the appropriate starting compounds the following productsmay be prepared:

Example: Product 1 8 5-bromo-1-(4,4 dibromobutyryl)-2-imino- 3-(2 bromo4 sulfamoylphenyD-3- indolinol. 9 Z-amino 5bromo-3-(2-bromo-4-sulfamoylphenyl -3 H-indol-3-ol. 10 Z-imino 1 (3iodopropiony1)-5-iodo-3- phenyl-3-indolinol. 112-amino-5-iodo-3-phenyl-3H-indol-3-ol. 12 s l-acetyl 3(m-chlorophenyl)-2-imino-7- sulfamoyl-3-ir1dolinol. 13 2-amino-3-(mchlorophenyl)-7-sulfamoyl- 3H-indol-3-ol. 14 2 imino 4 'methoxy 3 (mmethoxyphenyl -1-propionyl-3 -indoli-nol. 15 2 amino 4 methoxy 3 (mmethoxyphenyl -3H-indol-3 -ol. 16 5 -butanoxy 3 (m -butanoxyphenyl)-1butyryl-2-imino-3-indolinol. 17 2-amiino 5 butanoxy 3(m-butanoxyphenyl)-3H-indol-3-ol. 1 18 l-acetyl 6 ethoxy 3(2-ethoxy-4-iodophenyl) -2-imino-3 -indo1inol. 19 2-amino 6 ethoxy 3(2-ethoxy-4-iodophenyl) -3H-ind0l-3 -ol. 20 2-imino-5-methyl 3 (mtolyl)-1-pentanoyl-3-indolinol. 21 2-amino-5-methyl 3 (mtolyl)-1-pentanoyl-3H-indol-3-ol. 22 5-butyl-3-(m-butylphenyl) 1 (2chlorol acetyl) -2-imino-3-indolinol.

23 2-amino 5 butyl-3-(m-butylphenyl)-3H- indol-3-ol.

EXAMPLE 24 In a procedure similar to Example 7, 5-ch1oro-3-(2-chloro-S-sulfamoylphenyl) 1 (2,2 dichloroacetyl)-2- imino-3-indolinol isprepared from 2,2,4-trichloro-2'-(2-chloro-S-sulfamoylbenzoyl)acetanilide and potassium cyanide. The producthas a melting point of 2=0 3205 C. and is obtained as thehemi-alcoholate.

Arralysisr' calcd. for C1 H11C14N 3O4S- /2C2H O (percent): C, 40.33; H,2.79; N, 8.30; CI, 28.02; S, 6.34. Found (percent): C, 39.61; H, 3.03;N, 8.11; CI, 27.6; S, 6.7.

Also isolated from the reaction as the hemi-hydrate is 2amino-5-chloro-3-(2-chloro-5-sulfamoylphenyl)-3H- indol-3-0l.

Analysis.Calcd. for C H Cl N OSJ/2H O (percent): C, 44.10; H, 3.17; N,11.02; Cl, 18.60; S, 8.41. Found (percent): C, 44.29; H, 3.04; N, 10.95;CI, 18.6; S, 8.2.

EXAMPLES 2528 In like manner, following the procedure of Example 9EXAMPLE 29 The following example illustrates the preparation from acompound (IV) of a compound (V), the latter being2-amino-5-chloro-3-(2-chloro 5 sulfamoylphenyl)-3H- indol-3-ol.

A suspension of 1.9 g. of S-chloro-3-(2-chloro-5-sulfamoylphenyl) 1(2,2-dichloroacetyl)-2-imino-3-indolinol in 50 ml. of water is heatedwith 5 ml. of 4 N dilute sodium hydroxide. The mixture is heated on asteam bath for 1 hour and cooled. The cool reaction mixture is acidifiedby the addition of acetic acid, and a precipitate forms. The precipitateis filtered out and twice recrystallized from an alcohol-water mixture.The product, 2-amino-5- chlo ro-3- (2-chloro-S-sulfamoylphenyl-3H-indol-3-ol, has a melting point of 2l5216 C.

EXAMPLE 30 The following illustrates the preparation of a compound ofFormula VIII.

(A) A mixture of 2.8 grams of 2-amino-5-chloro-3- phenyl-3H-indol-3-ol,3.4 grams of di-methylaminoethyl chloride hydrochloride, 7 millilitersof triethylamine and 20 milliliters of dimethylformamide is refluxedwith stirring for one hour. When the reaction is complete, the reactionmixture is diluted with a large volume of water and decanted. Theinsoluble material is suspended in dilute acetic acid, filtered and thefiltrate neutralized with sodium carbonate. The product is5-chloro-2-[2-(dimethylamino) ethylamino] -3-phenyl-3H-indol-3-ol.

(B) The resultant free base is converted to hydrochloride salt in etherand recrystallized from acetonitrile yielding 1.5 grams of5-chloro-2-[2-(dimethylamine)ethylamino]-3-phenyl-3H-indol-3-ol,hydrochloride having a melting point of 247249 C. Recrystallization fromethanol results in a product which decomposes at 257- 258 C.

Based on the formula C H ClN O2I-ICL- /2H O, it is calculated that theelemental analysis by weight will be 52.50 percent carbon, 5.63 percenthydrogen, 10.21 percent nitrogen, 25.94 percent chlorine and 2.18percent water. The product is analyzed and the content is found to be52.68 percent carbon, 5.92 percent hydrogen, 10.02 percent nitrogen,25.5 percent chlorine and 2.09 percent water. The foregoing may beexpressed:

Analysis.-Calcd. for C H ClN O2I-ICL /2H O (percent): C, 52.50; H, 5.63;N, 10.21; C1, 25.94; H O, 2.18. Found (percent): C, 52.68; H, 5.92; N,10.02; Cl, 25.5; H O, 2.09.

EXAMPLES 31-45 Proceeding as described in Example 30A but reacting anappropriate 2-amino-3-aryl-3H-indol-3-ol with an appropriate loweralkyl, monoor di-(lower)alkylamino lower alkyl, affords the followingproducts:

Example: Product 31 2-[2-(diethylamino)ethylamino] 4-fluoro-3-(3-fiuoro5-sulfamoylphenyl) 6 sulfamoyl-3H-indol-3-ol.

32 -bromo-3-(m-bromophenyl) 2 [3-(dimethylamino)propylamino] 3H-indol-3-01.

33 2-[4-(dibutylamino)butylamino] 5 chloro-3- (m-chlorophenyl-3H-indol-3-ol.

34 5-iodo-3-(rn-iodophenyl) 2 dimethylaminomethylamino-3H-indol-3-01.

35 7-chloro-3-(3-chloro 5-sulfamoylphenyl)- 2-methylaminomethylamino 4sulfamoyl-3H-indo1-3-ol.

36 5-bromo-3-(m-bromophenyl) 2-[2-(ethylamino) ethylamino]-3H-indol-3-ol.

37 2-[4-butylamino)butylamino] 7-fluoro-3-(m-fluorophenyl)-3H-indol-3-ol.

38 5-iodo-3-(m-iodopheny1) Z-methylarninoethylamino-3H-indol-3-ol.

10 Example: Product 39 5-chloro-3(m-chlorophenyl)-2-[2-(ethylamino]-3H-indol-3-ol.

40 S-(m-butylphenyl) 2-methylamino-5-propyl-3H-indol-3-ol.

41 5-ethyl-2-ethylamino 3 (p-ethylphenyl)- 3H-indol-3-o1.

42 5-methyl-3-(m-methylphenyl) 2 pentylamino-3H-indol-3-ol.

43 B-(m-ethoxyphenyl)-5-methoxy 2-methylamino-3H-indol-3-ol.

44 5-ethoxy-3-(m-ethoxyphenyl) 2 ethylamino-3H-indol-3-ol.

45 5-butoxy-3 (m-butoxyphenyl) 2-propylamino-3H-indol-3-o1.

EXAMPLE 46 This example described the preparation of 5-chloro-3-methoxy-1-methyl-2-methylimino 3-phenylindoline, a trialkylsubstituted product having Formula VI.

To a suspension of 2.5 g. of 2-amino-5-chloro-3-phenyl- 3H-indol-3-ol in50 ml. of ethanol and 3 equivalents of alkali was added dimethyl sulfateuntil the reaction was no longer basic. The reaction mixture was thenmade basic with sodium hydroxide and diluted with ml. of water toproduce a sticky solid (1.5 g.). Two recrystallizations from anethanol-water mixture afforded the product,5-chloro-3-methoxy-1-methyl-2-methylimino-3- phenylindoline, having anM.P. 109-112.

Analysis.Calcd. for C H CIN O (percent): C, 67.88; H, 5.70; Cl, 11.79;N, 9.32. Found (percent): C, 68.55; H, 5.62; Cl, 11.80; N, 9.37.

EXAMPLES 47-49 Proceeding as described in Example 46 but substituting anappropriate dialkylsulfate and an appropriate 2-amino-3-phenyl-3H-indol-3-ol, the following products are afforded:

Example: Product 47 3-butoxy-1,5-dibutyl 2butylimino-3-(pbromophenyl)indoline.

48 3,6-diethoxy-l-ethyl-2-ethylimino 3 -(methylphenylindole) 495-fiuoro-3-(m-methyl p-sulfamoyDphenyl- 3-propoxy-l-propyl 2propyliminoindole.

EXAMPLE 50 This example describes the preparation of a monoalkylsubstituted product, 5-chloro-2-methylirnino-3-phenyl-3- indolinol, anda dialkylsubstituted product 5-chloro-3-methoxy-2-methylimino-3-phenylindoline, compounds of Formula VI.

Part A: To a suspension of 5.0 g. of Z-amino-S-chloro-3-phenyl-3H-indol-3-ol in 100 ml. of ethanol and 1.5 moles of alkali wasadded dimethyl sulfate until the reaction was neutral. The reactionmixture was made alkaline with sodium hydroxide, diluted with 200 ml. ofWater and the resultant semi-solid suspended in acetonitrile to afford1.2 g. of solid, M.P. 175178. Recrystallization from acetonitrileproduced 0.9 g. of S-chloro-Z-met-hyliminoG- phenyl-3-indolinol having aM.P. 179-181".

Analysis.-Ca1cd. for C H ClN O (percent): C, 66.06; H, 4.80; Cl, 13.00;N, 10.27. Found (percent): C, 65.80; H, 4.99; C1, 13.15; N, 10.15.

Part B: The acetonitrile solution from Part A, was concentrated todryness in vacuo to afford 1.1 g. 5chloro-3-methoxy-Z-methylimino-3-phenylindoline. Recrystallization from analcohol-water mixture and then from hexane gave the pure compound havinga M.P. -l22.

Analysis.Calcd. for C H ClN O (percent): C, 67.01; H, 5.27; Cl, 12.36;N, 9.77. Found (percent): C, 66.98; H, 5.31; C1, 12.50; N, 9.09.

1 1 EXAMPLES 51-53 Proceeding as described in Parts A and B of Example50 but substituting an appropriate dialkylsulfate and an appropriate2-amino-5-chloro-3-phenyl-3H-indol-3-ol the The following exampleillustrates the preparation of a compound having structural FormulaV=]1.

A solution of 2.0 g. of-chloro-3-(2-chloro-5-sulfamoylphenyl)-1-(2,2-dichloroacetyl)-2-imino-3-indolinol,ml. of hydrazine hydrate and 1-0 ml. of water is heated on the steambath for one-half hour. The reaction mixture is cooled, diluted withwater and acidified with acetic acid. The product is filtered, suspendedin acetonitrile and refiltered. After recrystallization fromethanolwater there is obtained 1.0 g. of 4-chloro-3-(5-chloro-2-hydrazino-3 hydroxy-3H-indol 3-yl)benzenesulfonamide having a meltingpoint of 195196 C.

Analysis.Calcd. for C H Cl N O S (percent): C, 43.42; H, 3.12; N, 14.47;Cl, 18.31; S, 8.28. Found (percent): C, 43.28; H, 3.23; N, 13.88; Cl,17.9; S, 8.5.

EXAMPLES 55 AND 56 Similarly following the procedure of Example 54, '5bromo 3 (2 hydrazino 3 hydroxy 3H indol- 3-yl)benzenesulfonamide; and 3(6 bromo 2 hydrazino 3 hydroxy 3H indol 3 yl) 6 methylbenzenesulfonamideare prepared.

EXAMPLE 5 7 The following example illustrates the preparation of acompound of Formula VII.

A mixture of 0.5 gram of 2-amino-5-chloro-3-phenyl- 3H-indol-3-ol, 5milliliters of hydrazine hydrate, 5 milliliters of Water and 20milliliters of ethanol are heated to reflux temperatures for one-halfhour and upon cooling yield 0.4 gram of white solid5-chloro-2-hydrazino-3- phenyl-3H-indole-3-ol, having a melting point of203- 204 (from ethanol). The product is solvated with onehalf mole ofethanol.

Analysis.Calcd. for C H ClN O- /2C H O: (percent): C, 60.71; H, 5.10; N,14.16. Found (percent): C, 60.68; H, 4.82; N, 14.31.

EXAMPLE 5 8 The following example illustrates the preparation of acompound having Formula VII.

A mixture of 0.8 gram of 2-amino-5-chloro-3 (2-chloro-S-sulfamoylphenyl)-3H-indole-3-ol, 8 milliliters of hydrazine hydrateand 8 milliliters of water are heated to refiux for one quarter hour.The solution is cooled, diluted with an equal volume of water, filteredfrom impurities and acidified with acetic acid. The reaction mixture ischilled overnight and 0.7 grams of 6-chloro-3-(2-chloro-5-sulfamoylphenyl)-2-hydrazino 3 hydroxy-3H-indole- S-sulfonamide havinga melting point of 212213 (decomposes) is obtained.

Analysis.Calcd. for C14H13C12N5O5S2 (percent): C, 36.06; H, 2.81; N,15.01; S, 13.75. Found (percent): C, 35.53;H, 2.85;N, 14.60; S, 13.30.

EXAMPLE 5 9 The following example illustrates the preparation of acompound having Formula VII.

A solution of 1.0 g. of1-acetyl-2-imino-3-(S-sulfamoylphenyl)-3-indolinol, 5 ml. of hydrazineand 5 ml. of water is heated at 60 C. for four hours. The reactionmixture is cooled, diluted with water and acidified with citric acid.The product is filtered, suspended in acetonitrile and refiltered. Afterrecrystallization from methanol-water there is afforded3-(2-hydrazino-3-hydroxy-3H-indol-3-yl) benzenesulfonamide.

EXAMPLE 60 The following example illustrates the preparation of acompound having Formula VII.

A solution of 20.0 g. of 3 (4 chlorophenyl) 1 (2- chloroacetyl) 2 imino5 methoxy 3 indolinol, ml. of hydrazine hydrate and 100 ml. of water isheated on the steam bath for one hour. The reaction mixture is cooled,diluted with water and acidified with acetic acid. The product isfiltered, suspended in acetonitrile and refiltered. Afterrecrystallization from propanol-water there is obtained3-(4-chlorophenyl)-2-hydrazino 5 methoxy- 3H-indol-3-ol.

EXAMPLE 61 In like manner to that of Example 601-(2,2-dichloroacetyl)-2-imino-6-methyl-3-(4-tolyl) 3 indolinol isconverted to 2 hydrazino 6 methyl-3-(4-tolyl)-3H-indol- 3-01.

EXAMPLES 62-70 Repeating the procedure described in Example 54 to reactan appropriate 3-aryl-1-(dihaloalkanoyl)-2-imino-3- indolinol withhydrazine, the following compounds are obtained:

Example: Product 626-ethyl-3-(4-fluoropenyl)-2-hydrazino-3-H-indol-3-ol.

63 2-hydrazino-3-phenyl-3H-indol-3-ol.

64 2-hydrazino-3-(4-iodophenyl)-3H- indol-3-ol.

65 5-ethoxy-2-hydrazino-3-(3-methoxyphenyl)-3Hindol-3-ol.

66 3-(4-butoxyphenyl)-2-hydraZino3H- indo1-3-ol.

67 5-fiuoro-2-hydrazino-3-phenyl-3H- indol-3-ol.

68 2-hydrazino-3-(iodophenyl)-6- propyl-3H-indol-3-ol.

69 3-(4-ethoxyphenyl)-2-hydrazino-3H- indol-3-ol.

70 2-hydrazino-3-(4-pr0pylphenyl)-3H- indol-3-ol.

The terms and expressions which have been employed are used as terms ofdescription and not of limitation, and there is no intention in the useof such terms and expressions of excluding any equivalents of thefeatures shown and described or portions thereof, but it is recognizedthat various modifications are possible within the scope of theinvention claimed.

What is claimed is:

1. A compound selected from those having the formula where R and R arethe same or different members selected from the group consisting ofhydrogen, halogen, lower alkyl and lower alkoxy;

R and R are the same or different members selected from the groupconsisting of hydrogen and sulfamoyl;

R is selected from the group consisting of hydrogen,

lower alkyl, lower alkylamino(lower) alkyl, and di (lower) alkylamino(lower) alkyl;

R is selected from the group consisting of hydrogen and lower alkyl; and

R is selected from the group consisting of hydrogen, lower alkyl, loweralkanoyl, halo (lower) alkanoyl, and dihalo(lower)alkanoyl, with theproviso that when R R and R are lower alkyl they are the same.

2. A compound as defined in claim 1 which is5-chloro-1-2,2-dichloroacetyl) -2-imino-3-(m sulfam0ylphenyl)-3-indolinol.

3. A compound as defined in claim 1 which is S-chloro-3-2-chloro-5-sulfamoylphenyl) 1- 2,2 dichlorocetyl) 2-imino-3-indolinol.

4. A process for the preparation of a compound selected from the groupof those having the formula which comprises contacting a2-benzoylacylanilide of the formula R NHCORB R o=o with an ionic cyanideselected from the group consisting of sodium cyanide, lithium cyanide,calcium cyanide, cuprous cyanide and potassium cyanide in the presenceof a proton donor for a period of about 15 minutes to about 72 hours ata temperature range from about 0 C. to about 50 C.

where R and R are the same or different members selected from the groupconsisting of hydrogen, halogen, lower alkyl and lower alkoxy;

R and R are the same or different members selected from the groupconsisting of hydrogen and sulfamoyl; and

R is lower alkyl, halo(lower)alkyl, or dihalo(lower) alkyl.

5. A process as defined in claim 4 further comprising the steps ofhydrolyzing the reaction product and alkylating the resultant product toobtain a compound selected from those having the formula l R1 /N R2 ILwhere R is hydrogen or lower alkyl; R is hydrogen or lower alkyl; and Ris lower alkyl, with the proviso that when R R and R are lower alkyl,they are the same.

6. A process as described in claim 5 where the ionic cyanide ispotassium cyanide and the proton donor is Water.

7. A compound as defined in claim 1 which isS-chloro-2-[2-(dimethylarnino)ethylamino] 3 phenyl-3H-indol-3-ol.

8. A compound as defined in claim 1 which isS-chloro-3-methoxy-1-methyl-2-methylimino-3-phenylindoline.

9. A compound as defined in claim 1 which isS-chloro-3-methoxy-2-methylimino-3-phenylindoline.

References Cited UNITED STATES PATENTS 3,441,570 4/1969 Meyer 260-325ALEX MAZEL, Primary Examiner J. A. NARCAVAGE, Assistant Examiner U.S.Cl. X.R.

@2 3? W/UNITED STATES PATENT OFFICE IERTIFICATE OF CORRECTION Patent No.3,577 %5 Dated y 1 Inventor(s) Stanlev C. Bell and Carl Gochman It iscertified that error appears in the above-identified patent and thatsaid Letters Patent are hereby corrected as shown below:

zitructure f at the top of columns 3, i should read:

@2 3? UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. Q577. 3 Dated 19:71

Inventofls) Stanley C l and Carl Gochman PAGE 2 It is certified thaterror appears in the above-identified patent and that said LettersPatent are hereby corrected as shown below:

r In column 12, formula. in Claim 1 should read:

In column 1 formula in Claim 5 should read:

Signed and sealed this 1 7th day of August 1971 (SEAL) Attest;

EDWARD M.FLETCHER,JR. WILLIAM E. SCHUYLER, JR.

Attesting Officer Commissioner of Patents

